title: High-throughput respirometric assay identifies predictive toxicophore of mitochondrial injury.
abstract: Many environmental chemicals and drugs negatively affect human health through deleterious effects on mitochondrial function. Currently there is no chemical library of mitochondrial toxicants, and no reliable methods for predicting mitochondrial toxicity. We hypothesized that discrete toxicophores defined by distinct chemical entities can identify previously unidentified mitochondrial toxicants. We used a respirometric assay to screen 1760 compounds (5 μM) from the LOPAC and ChemBridge DIVERSet libraries. Thirty-one of the assayed compounds decreased uncoupled respiration, a stress test for mitochondrial dysfunction, prior to a decrease in cell viability and reduced the oxygen consumption rate in isolated mitochondria. The mitochondrial toxicants were grouped by chemical similarity and two clusters containing four compounds each were identified. Cheminformatic analysis of one of the clusters identified previously uncharacterized mitochondrial toxicants from the ChemBridge DIVERSet. This approach will enable the identification of mitochondrial toxicants and advance the prediction of mitochondrial toxicity for both drug discovery and risk assessment.
authors.affiliation: MitoHealth Inc., Charleston, SC 29403, USA.
authors.forename: Lauren P
authors.initials: LP
authors.lastname: Wills
authors.forename: Gyda C
authors.initials: GC
authors.lastname: Beeson
authors.forename: Richard E
authors.initials: RE
authors.lastname: Trager
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Lindsey
authors.forename: Craig C
authors.initials: CC
authors.lastname: Beeson
authors.forename: Yuri K
authors.initials: YK
authors.lastname: Peterson
authors.forename: Rick G
authors.initials: RG
authors.lastname: Schnellmann
mesh_terms: D000818:Animals; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D002470:Cell Survival; D004785:Environmental Pollutants / Q000737:chemistry / Q000633:toxicity*; D005260:Female; D057166:High-Throughput Screening Assays / Q000379:methods*; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010101:Oxygen Consumption / Q000187:drug effects*; D011237:Predictive Value of Tests; D061251:Primary Cell Culture; D061209:Proton Ionophores / Q000494:pharmacology; D011817:Rabbits; D054852:Small Molecule Libraries / Q000737:chemistry / Q000633:toxicity*; D013329:Structure-Activity Relationship
chemical_list: D004785:Environmental Pollutants; D061209:Proton Ionophores; D054852:Small Molecule Libraries; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone
keywords: ChemBridge; LOPAC; Mitochondria; Renal proximal tubule cells; Seahorse Biosciences Extracellular Flux; Toxicophore